The "macrocosm" of our society that is exposed to chemicals, such as polycyclic aromatic hydrocarbons (PAH's) and polychlorinated biphenyls (PCB's), represents a significant public health problem. Developmental neurotoxicity seems to be achieving a leading role and may even displace cancer as the basis for assessing the human risks posed by exposure to these types of environmental mixtures. Very little is known with regard to the effects of these mixtures on brain developmental gene expression. The temporal and spatial regulation of gene expression is a critical component of neuro-biological development and as such, may be a mediator of PAH/PCB neurotoxicity. Data obtained from our laboratory on the temporal and spatial regulation of gene expression in the brain indicate that subsequent to PAH aerosol exposure (1) Sp1 DNA-binding is developmentally regulated and expressed very highly in actively developing brain regions, and (2) a consequence of the transplacental deposition of desorbed PAH to the fetus is in utero neurotoxicity. Because the molecular level mechanism of PAH and PCB toxicity is mediated by the aryl hydrocarbon receptor, these data support the concept that PAH's and PCB's can alter developmental gene expression through interference with transcription factors. The primary objective of this proposal is to study the synergistic mechanism by which mixed transplacental exposures [PAH (aerosol)/PCB (gavage)] influence developmental gene expression; and to correlate genotypic "immediate early" alterations with phenotypic neuronal "late responses". This objective will be addressed within the context of a central hypothesis which states that synergistic alterations in developmental gene expression the brain occur as a result of mixed transplacental exposures [PAH (aerosol)/PCB(gavage] to ultimately result in altered cognitive function. The results from these studies will contribute to an understanding of the neuro-biological mechanisms by which constituents of mixed exposures mediate adverse acute neurological health effects.